Various medical interventions involve inhibiting monoamine transport and/or inhibiting binding to monoamine receptors. One example concerns cocaine, a potent stimulant of the mammalian central nervous system. Cocaine's reinforcing and stimulant properties have been associated with its propensity to bind to the dopamine. transporter (DAT). Such binding causes an inhibition of dopamine (DA) transport and a subsequent increase in concentration of extracellular DA for activation of postsynaptic receptors. Cocaine inhibition of dopamine transport and the resulting surge in extracellular dopamine levels is thought to be a major contributor to the stimulant and reinforcing properties of cocaine.
One approach considered for treating cocaine dependence involves cocaine congeners that prevent cocaine binding to the dopamine transporter. A significant problem associated with the use of cocaine congeners is that (like cocaine) the congeners tend to block dopamine reuptake and thereby elevate extracellular dopamine levels. In that way, congeners may produce reinforcing effects by the same mechanism that cocaine does, with a consequent potential for abuse. Madras et al., J. Pharmacol, Exp. Ther., 251:131-141 (1989); Bergman et al., J. Pharmacol, Ther., 251:150-155 (1989).
It has therefore been a goal of research to discover a molecule that can inhibit cocaine binding to the DAT but continue to allow DA transport by the DAT. While the cocaine inhibitor would still bind to the DAT, it would affect the rate of reuptake of DA by this transporter to a lesser extent. In this manner, the concentration of DA in the synapse would remain at normal physiological levels. It would be useful to discover molecules that can inhibit binding of certain compounds to the transporter or receptor but continue to allow transport of desired ligands through the transporter.
Similarly, it would be useful to block entry of other types of addictive drugs, e.g. MDMA, methamphetamine, amphetamine, that are similar to but not identical with the natural monoamine transmitters to the cell interior without blocking serotonin, norepinephrine or dopamine transport.
In these instances, it would be desirable to have an antagonist that is not simply a molecule that will inhibit binding of the drug at the transporter, but more importantly, it will permit transport of synaptic DA to the presynaptic neuron.
Most antagonists bind the transporter or receptor and prevent the binding or transport of all other molecules or substrates, even those that are. desirable to be transported. Thus, it would be useful to have compounds that prevent the transport or binding of certain compounds to the transporter or receptor but allow others to pass through.
There are also instances where it would be useful to have partial blockage of transporters or receptors to decrease the transport of substances whose build up results in negative effects. For example, Parkinsonism can be caused by entry of a neural toxin called MPP+ (1-methyl-4-phenylpyridine) into dopamine cells in the brain. It would be useful to have a mechanism that impedes the entry of MPP+ or other dopamine neuron toxins into dopamine cells without blocking access of dopamine. Such a compound can be used as a neuroprotective agent, if a neurotoxin is involved and uses the dopamine transporter.
For the treatment of schizophrenia, partial agonists have been assessed that target dopamine receptors. In contrast, agonists presently used, e.g. D2-D3 dopamine receptor antagonists, produce negative side effects such as muscle stiffness and unintended movements, as well as an inability to still restless legs. Presently used antipsychotic drugs act by modulating dopamine and other neurotransmitter signaling systems in the brain. The basic mechanism of conventional antipsychotic drugs is to reduce the effects of dopamine. This is achieved by drug blockade of D2 receptors on the dopamine-responding cells. By analogy to the DAT, partial blockade at the dopamine receptors by a drug may be useful to treat schizophrenia but allow partial use of dopamine that is necessary for normal cell function.
Selective serotonin re-uptake inhibitors (SSRIs) are a group of drugs used to treat major depression, dysthymia, panic disorder, obsessive-compulsive disorder, eating disorders, and premenstrual dysphoric disorder. They include citalopram (Cipramil), fluoxetine (Prozac), fluvoxamine (Faverin), paroxetine (Seroxat), and sertraline (Lustral). In these diseases, e.g., depression, the levels of neurotransmission in the brain are disturbed. SSRIs elevate serotonin levels, by reducing its uptake through serotonin transporters (SERT) into brain cells. People who take SSRIs may experience side effects including gastrointestinal disturbances, headache, sedation, insomnia, activation, weight gain, impaired memory, excessive perspiration, paresthesia, and sexual dysfunction. The side effects are due in part to inhibition of sertonin transport in the brain.
Tricyclic antidepressants, (commonly called TCAs) are also prescribed for depression. Examples of TCAs are: imipramine (Tofranil), amitriptyline (Elavil) and nortriptyline (Pamelor). TCAs work by raising the levels of serotonin and norepinephrine in the brain by slowing the rate of reuptake, or reabsorption, by nerve cells. TCAs tend to have more unpleasant side effects than the newer antidepressants such as SSRIs. The side effects of TCAs vary with the specific medication taken and the individual. Some typical side effects include drowsiness, anxiety, restlessness, dry mouth, constipation, urinary retention, difficulty urinating, cognitive and memory difficulties, weight gain, increased sweating, dizziness, decrease in sexual ability and desire, muscle twitches, fatigue, weakness, nausea, increased heart beats, irregular heart rhythms (very rare). Thus, it would be useful to have a mechanism to reduce certain side effects of tricyclic antidepressants and SSRI's, e.g., by allowing partial transport of serotonin that is necessary for normal cell function.
Thus, it would be useful to have a general mechanism by which transport of endogenous and exogenous ligands through certain transporters can be controlled.